Is this your (paediatric patient's) brain on (anaesthetic) drugs?: The search for a potential neurological phenotype of anaesthesia-related neurotoxicity in humans

From the Department of Anesthesiology, University of Cincinnati College of Medicine, Division of Pediatric Cardiac Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA (AWL), and Department of Anesthesiology and Intensive Care, Odense University Hospital, and Clinical Institute, Anesthesiology, University of Southern Denmark, Odense, Denmark (TGH)

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This Invited Commentary accompanies the following original article:Ko W-R, Huang J-Y, Chiang Y-C, et al. Risk of autistic disorder after exposure to general anaesthesia and surgery. A nationwide, retrospective matched cohort study. Eur J Anaesthesiol 2015; 32:303–310.A popular advertising campaign in the 1980s and 1990s illustrated the dangers of drug and alcohol abuse for the teenage brain by showing a raw egg (‘This is your brain’) being cracked and fried in a pan (‘This is your brain on drugs’). In a sense, this was a simplified representation of the phenotype of drug use in the developing teenage brain (https://www.youtube.com/watch?v=ub_a2t0ZfTs; Accessed June 2014). Currently, researchers are trying to identify whether there exists a neurological phenotype following early childhood exposure to a class of therapeutic drugs, anaesthetics and sedatives. Concerns for potential harmful effects of anaesthetics on brain development in young children undergoing surgical procedures were first raised by animal studies demonstrating widespread cell death of neurones and oligodendrocytes, reductions in neurotrophic factors, alterations in synaptic and dendritic densities, disintegration of the cytoskeleton and long-term neurocognitive impairment following anaesthetic exposure early in life.1 Subsequently, epidemiological studies established an association between surgical exposure during the first 3 to 4 years of life with learning disabilities, behavioural and developmental disorders or academic underachievement. However, potent confounders, such as the surgical procedure, the underlying illness, postoperative pain and inflammatory response preclude establishing any causative relationship. Fortunately for patients and practitioners, the effect on neurocognitive outcome is not obvious enough to cause overt mental retardation in all children undergoing surgery, and several studies did not even observe any subtle effects until children were exposed more than once. Complicating the search for a potential phenotype is the fact that it is currently unclear whether certain neurological domains or specific cognitive skills, such as reading, writing, arithmetic or executive function, are specifically affected following exposure.The biological plausibility for potential interference with brain development is rooted in the potent effects of anaesthetic drugs on glutamate's NMDA (N-methyl-D-aspartate) and/or GABA (γ-aminobutyrate) receptors, both of which play critical roles in normal brain development. During brain development, GABA directs cell proliferation, neuroblast migration and dendritic maturation.2 Developmental NMDA receptor stimulation fosters survival and maturation of some neurones.3 Moreover, the relative contributions of these two main excitatory and inhibitory neurotransmitters, respectively, are instrumental in maintaining the adequate balance of excitation and inhibition, which is vital for proper brain function and could be altered by exposure to anaesthetics.4 Many childhood surgical procedures occur under 3 to 4 years of age and are predominantly performed in boys.5It seems sensible, therefore, to examine whether early interference with NMDA and GABA receptor signalling in childhood may lead to subsequent neurodevelopmental disorders, such as autism spectrum disorder (ASD). Autism spectrum disorder is a heterogeneous disability diagnosed with an increasing frequency (1.5% of U.S. children) that includes abnormalities in communication, behaviour, language or intellectual abilities. Early deficits in communicative and social skills are often observed prior to 18 months of age, and boys are more frequently afflicted than girls by a factor of 4 : 1. Possible aetiological factors include not only genetic components (with a reported heritability of 90%), but also prenatal and environmental factors. Importantly, it has been speculated that this disorder may arise from an abnormal ratio of excitatory to inhibitory neurotransmitters in the brain.6 The current diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) distinguish between three categories: autism disorder; Asperger's syndrome; and not otherwise specified pervasive developmental disorder (‘atypical autism’).